Abstract
Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
Highlights
Gorham-Stout disease (GSD) is a sporadically occurring disorder of the lymphatic system [1]
We show that hyperactive KRAS signaling in lymphatic endothelial cells (LECs) in mice stimulates the development of lymphatic vessels in bone, impairs the development of lymphatic valves, and causes chylothorax
We report the identification of a somatic activating mutation in KRAS (c.35G>T, p.G12V) in a tissue sample from a patient with GSD
Summary
Gorham-Stout disease (GSD) is a sporadically occurring disorder of the lymphatic system [1]. Since the first demonstration in 2009 that sporadically occurring venous malformations are caused by somatic activating TIE2 mutations, various sporadically occurring lymphatic and vascular anomalies have been associated with somatic activating mutations [8]. The majority of these mutations are identical to. We show that an FDA-approved MEK1/2 inhibitor, trametinib, suppresses lymphatic valve regression in our mouse model Together, these findings pinpoint RAS signaling in the etiology of GSD and suggest that MEK inhibitors could be used as a treatment for this life-threatening disease
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.